Search

Charcot-Marie-Tooth (CMT) disease represents a distinct subgroup of inherited peripheral neuropathies with a significant prevalence throughout the world and manifests both phenotypic and genetic heterogeneity. Electrophysiological studies subclassify CMT mainly as demyelinating or axonal types. In this study, we investigated the molecular characteristics of a Turkish cohort of 23 probands out of 34 symptomatic demyelinating CMT individuals from January 2019 to December 2021. In order to identify the underlying genetic cause, we applied a rational algorithm: PMP22 gene was initially analyzed for duplication, if PMP22-duplication testing was negative, other most causative genes (GJB1, MPZ) and PMP22 were then sequenced and if no variant was detected at aforementioned tests, whole exome sequencing (WES) test was finally performed. A total of 17 patients (≅ 74%; n = 23) were found to harbor a disease-causing variant in demyelinating CMT-related genes and among the variants, PMP22-duplication was the most frequent (≅ 41%). CMT1, CMTX, and CMT4 subtypes were manifested in ten, five, and two individuals respectively. GJB1 and SBF2 genes were the only detected genes associated with the CMTs other than CMT1. We also reported totally five novel variants: c.379A C (p.Ile127Leu) and c.548G T (p.Arg183Leu) variants in GJB1, c.988G T (p.Glu330Ter) variant in NEFL, c.765_770delCCCTAT (p.Pro256_Ile257del) and c.2552A C (p.His851Pro) variants in SBF2. As the understanding of pathophysiology and molecular mechanisms of CMT continues to evolve rapidly, many therapeutic strategy options including promising small-molecular compounds, gene replacement therapy, or disease-modifying therapies will soon be implemented in the clinical setting.

PURPOSE: Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients. METHODS: A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype, FMR1 premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients. RESULTS: A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and FMR1 premutation was detected in six patients (17%) from two different families. A total of 29 patients without FMR1 premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including PARK2 gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29). CONCLUSION: In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.

AMAÇ: Karaciğerin fibrokistik hastalıkları (KFKH); intrahepatik ve/veya ekstrahepatik biliyer anormallikler sonucunda safra kanallarında genişleme, hepatik fibrozis ve kistik oluşumlarla karakterize olan kalıtsal geçişli nadir görülen bir hastalık grubudur. Hastalar asemptomatik olabileceği gibi kolanjit, portal hipertansiyon, siroz, ele gelen kitle gibi semptomlarla başvurabilirler. Çalışmamızda; kliniğimizde takipli, KFKH olan hastaları; demografik özellikleri, klinik-laboratuvar bulguları ve son durumları ile değerlendirdik.GEREÇ VE YÖNTEMLER: Çalışmamıza; Ocak 2008- Aralık 2019 yılları arasında, Çocuk Gastroenteroloji, Hepatoloji ve Beslenme polikliniğinde KFKH nedeniyle takipli olan hastalar; klinik-laboratuvar bulguları, tedavi yaklaşımları ve son durumları ile geriye dönük olarak incelendi.BULGULAR: Toplam 39 hasta incelendi (%56.4 erkek, ortanca yaş; 5 yıl 3 ay, yaş aralığı: 1 ay-16.8 yıl). Sekiz hastada (%20.5) Caroli hastalığı (CH), 16 hastada konjenital hepatik fibrozis (KHF) (%41), 15 hastada koledok kisti tespit edilmişti. Başvuru şikayeti; en sık sarılık (n=8, %20.5), kronik karın ağrısı (n=6, %15.4) ve splenomegali (n=4, %10.3) idi. Sekiz hasta renal kist tespiti sonrası taramada (%20.5), yedi hasta intrauterin dönemde (%17.9), iki hasta ise insidental olarak tespit edilmişti (%5.1). Otozomal resesif polikistik böbrek hastalığı (ORPBH) olan altı hastada PKHD1 gen mutasyonu saptandı. On sekiz hasta opere edildi (%46.2, karaciğer nakli, sol lol segmental hepatektomi, mezokaval şant, böbrek nakli, kistektomi). 25 hastaya (%64.1) eşlik eden başka hastalıklar mevcuttu; 18’inde (%46.2) ORPBH, ikisinde metal motor retardasyon (%5.1; birinde metokromatik lökodistrofi, diğerinde Arnold Chiari malformasyonu), birer hastada (%2.6) nefrokalsinozis, juvenil nefronofitizis (böbrek nakli), akut pankreatit, pulmoner-metakarpal distal falanks hipoplazisi ve birinde medüler sünger böbrek ve pineal kist mevcuttu. Takip edilen 39 hastanın altısında portal hipertansiyon, beşinde kronik böbrek yetmezliği (%12.8), dördünde kompanse kronik karaciğer hastalığı (%10.3) ve birinde tekrarlayan kolanjit atakları (%2.6) olup CH olan bir hastaya dekompanse siroz nedeniyle karaciğer nakli yapılmıştı. TARTIŞMA: Karaciğerin fibrokistik hastalıkları; morbiditesi ve ileri dönem komplikasyon riski yüksek olan bir hastalık olması nedeniyle erken tanı konup düzenli takip yapılmalıdır., Objective: Fibrocystic liver disease (FLD) is a multisystemic disease that can be seen in a wide age range from intrauterine period to adolescent age. The aim of study is to evaluate the presenting symptoms, clinical-laboratory findings, treatment modality and results of the patients with FLD .Material and Methods: The demographic features, clinical-laboratory findings, treatment modality and results of patients with FLD followed up in our clinic between January 2008 and December 2019 were recorded retrospectively. Results: A total of 39 patients (56.4% male, median age; 53m years, age range: 10 days-16.8 years) were evaluated. Eight patients (20.5%) had Caroli’s disease (CD), 16 patients had congenital hepatic fibrosis (CHF) (41%), and 15 had choledochal cysts. The most common presenting symptoms were jaundice (n=8, 20.5%), chronic abdominal pain (n=6, 15.4%) and splenomegaly (n=4, 10.3%). Eight patients were detected after renal cyst detection and screening programme (20.5%), seven patients during intrauterine period (17.9%), and two patients incidentally (5.1%). PKHD1 gene mutation was deteceted in six patients with autosomal recessive polycystic kidney disease (ARPKD). Eighteen patients underwent surgical operation (46.2%, liver transplantation, left lobe segmental hepatectomy, mesocaval shunt, kidney transplantation, cystectomy). 25 patients (64.1%) had extrahepatic involvement [ ARPKD (n=18), mental motor retardation (n=2, methochromatic leukodystrophy, Arnold Chiari malformation in each one), nephrocalcinosis (n=1), juvenile nephronophytosis (n=1) acute pancreatitis (n=1), pulmonary hypoplasia + metacarpal distal phalanx hypoplasia (n=1) and medullary sponge kidney+pineal cyst (n=1)]. During the follow up of 39 patients; six patients had portal hypertension, five had chronic renal failure (12.8%), four had compensated chronic liver disease (10.3%) and one had recurrent cholangitis attacks (2.6%). Two patients underwent liver transplantation due to decompensated cirrhosis, and one patient underwent kidney transplantation due to end-stage renal failure. Conclusion: Early diagnosis, regular follow-up and treatment are important in patients with FLD because of the high risk of morbidity and complications.

OBJECTIVES: This study aims to evaluate the plasma expression of microribonucleic acids (miRNAs) that may be associated with the pathogenesis of familial Mediterranean fever (FMF). PATIENTS AND METHODS: Thirty patients with FMF (18 males, 12 females; mean age 9.1±4.7 years; range, 3 to 15.5 years) and 30 age- and sex-matched healthy children (18 males, 12 females; mean age 9.5±4.6 years; range, 4 to 16.5 years) were included in this study. The plasma levels of four candidate miRNAs (miRNA-16, miRNA-155, miRNA-204 and miRNA-451) were measured in all subjects. The plasma levels of miRNAs were analyzed with real- time polymerase chain reaction in attack and remission periods of patients and healthy controls (HCs). RESULTS: Plasma miRNA-204 levels of FMF patients were decreased 6.5 fold in remission period compared to HCs (p

Chromosomal microarray analysis (CMA) is a first step test used for the diagnosis of patients with developmental delay, intellectual disability, autistic spectrum disorder, and multiple congenital anomalies. Its widespread usage has allowed genome-wide identification of copy number variations (CNVs). In our study, we performed a retrospective study on clinical and microarray data of 237 patients with developmental disabilities and/or multiple congenital anomalies and investigated the clinical utility of CMA. Phenotype-associated CNVs were detected in 15.18% of patients. Besides, we detected submicroscopic losses on 14q24.3q31.1 in a patient with speech delay and on 18q21.31q21.32 in twin patients with seizures. Deletions of NRXN3 and NEDD4L were responsible for the phenotypes, respectively. This study showed that CMA is a powerful diagnostic tool in this patient group and expands the genotype-phenotype correlations on developmental disabilities.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an early onset systemic autoimmune genetic disorder caused by mutation of the forkhead box protein 3 (FOXP3) gene. Enteropathy, endocrinopathy and skin manifestations are considered the classic triad of IPEX syndrome. However, the patients with IPEX syndrome display a variety of phenotypes including life threatening multi-organ autoimmunity. Here, we present the case of two siblings with IPEX syndrome with the same hemizygous mutation, but with different types of symptomology at onset of the disease.

Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder associated with expanded CAG repeat size in the huntingtin gene and usually presenting with movement disorder, psychiatric symptoms, and cognitive decline. Sleep problems, weight loss, and cachexia are also common. Here, we report a patient presenting with hypothermia in late-stage HD. Although thermoregulatory defects were documented in animal models, this is the first report describing HD with hypothermia in humans.

CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population.

Particular fibrinogen gamma chain mutations occurring in the gamma-module induce changes that hamper gamma-gamma dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen gamma chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the gamma chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen gamma chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen gamma chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (Delta Delta G) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other gamma-module mutations causing HHHS.

Immunoglobulin A vasculitis (IgAV) is the most common form of childhood systemic vasculitis. It is mostly self-limiting and characterized by skin, joint, gastrointestinal tract, and kidney involvement. Microribonucleic acids (miRNAs) are 18-25 base-long non-coding RNA group acting on gene expression. They have been shown to be effective on the immune system studies to date.In our study, 24 IgAV children with skin and joint involvement and 24 healthy children were included. Five different miRNAs (miR-33, miR-34, miR-122, miR-204, and miR451) known to be expressed in plasma and related with autoimmunity pathogenesis were evaluated. miRNAs were compared between the active period of the disease, the post-treatment period, and the healthy group using the real-time PCR method.Expression levels of miRNA-33 and miRNA-34 increased significantly in active period of the patients compare with inactive period and control groups. The expression levels of miRNA-122 and miRNA-204 decreased significantly in active period of the patients compare with other two groups. There was no significant difference in miRNA-451 levels.With the experience we gained from our recent studies, we think that miRNA-204 may be a significant biomarker in autoimmune diseases. Our study is the first study between IgAV and miRNAs in children. More studies are needed to reveal this relationship. Key Points • This is the first paper to show the relationship between miRNAs and childhood IgAV. • It will provide a new perspective to evaluate the pathogenesis of the disease.

Objective: To determine the circulatory miRNA expression levels in patients with Hashimoto thyroiditis (HT) at the time of diagnosis and follow-up period compared with healthy controls. Methods: We collected blood samples from 34 patients with HT (4 males and 30 females) at the time of first diagnosis (Group P) and euthyroid period (Group E). Thirty-three healthy controls (Group H) blood samples were also included in the study. Expression levels of five different circulating miRNAs (miR-22, miR-141, miR-155, miR-375, miR-451) were evaluated using real-time polymerase chain reaction. Results: There was a significant difference in miR-375 levels between the groups P and H. Also, for miR-451, there was a significant difference between the P and E groups. Finally, there was a moderate positive correlation between thyroid-stimulating hormone values and miR-22 expression levels for the P group. Conclusion: miRNAs have important roles at all stages of the diseases. More studies must be performed in all thyroid diseases and autoimmune diseases, including HT.

Amaç: Bu çalışmanın amacı, bcr-abl negatif kronik miyeloproliferatif hastalık tanısı alan hastaların tanı anında JAK2 V617F, kalretikulin (CALR tip-1 ve tip-2) ve MPL-W515K / L mutasyonların sıklığını ve bu mutasyonların klinik önemini tartışmaktır.Gereç ve Yöntem: Bu çalışmada, Temmuz 2017-Mart 2019 tarihleri arasında BCR-ABL negatif kronik miyeloproliferatif hastalık tanısı alan hastaların demografik özellikleri, tanı alt tipi, risk durumu ve mutasyon analizi araştırılmıştır.Bulgular: JAK2-V617F mutasyonu 18‘i (% 85,7) polistemia vera (PV) ve geri kalanı (N = 9, %56,2) esansiyel trombositoz (ET) tanısı alan toplam 27 hastada saptandı. ET tanısı konmuş JAK2 V617F negatif 4 (% 57,1) hastada kalretikulin mutasyonu saptandı. Üç hastada CALR-tip 1 mutasyon ve 1 hastada CALR-tip 2 mutasyon tespit edildi. ET tanısı alan hastaların hiçbirinde MPL-W515K / L saptanmadı. Trombotik olay PV' li hastaların % 12,6'sı ve ET' li hastaların% 6,25'i olarak tespit edildi. Hastaların 14'ünde (% 37,8) splenomegali saptandı. Sonuç: Kronik myeloproliferatif hastalıkların patogenezi, sınıflandırılması ve risk grupları son yıllarda bazı genetik mutasyonların tanımlanması ile iyi karakterize edilmiştir. JAK2 V617F, CALR ve MPL kronik myeloproliferatif hastalıkların patogenezinde, hastalığın tanı, risk sınıflandırması, takipte önemli olan ve kişiselleştirilmiş tıpta önem kazanan aynı zamanda en sık tanımlanan somatik mutasyonlardır., Purpose: The aim of this study to discuss frequency and clinical significance of JAK2-V617F, Calreticulin (CALR type 1 and type-2) and MPL-W515K/L mutations in patients at initial diagnosis of bcr-abl negative chronic myeloproliferative diseases (CMPD).Materials and Methods: In this study, the demographic characteristics, subtype, risk status and mutation analysis were investigated between July 2017 and March 2019 in patients diagnosed with bcr-abl negative CMPD.Results: JAK2 V617F mutation was detected in sum of 27 patients, 18 of them (85,7%) diagnosed with polycythemia vera (PV) and rest of them (N=9, 56,2%) diagnosed with essential thrombocytosis (ET). Calreticulin mutation was positive in 4 (57,1%) patients, who were also JAK2 V617F negative, diagnosed with ET. CALR-type 1 mutation was detected in three patients and CALR-type 2 was in one. MPL-W515K/L was not detected in any of patients diagnosed with ET. Thrombotic event was accompanied 12,6% of patients with PV and 6,25% patients with ET. Splenomegaly was noted in 14 (37,8%) of patients. Conclusion: Pathogenesis, classification, and risk groups of CMPD have been well characterized with the identification of some genetic mutations in recent years. JAK2 V617F, CALR and MPL are the most common somatic mutations in the pathogenesis of CMPD, which are important in the diagnosis, risk classification and follow-up of the disease and gain importance in personalized medicine.

Introduction Adenomatous polyps in the gastrointestinal system rarely occur in childhood and are accompanied by syndromes such as Familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis, Gardner and Turcot syndrome, and also mismatch repair (MMR) gene defects. In this article, we want to present a rare patient who had adenomatous polyposis and in situ carcinoma and was detected biallelic MMR gene defect. Case A 16-year-old female patient admitted with painless rectal bleeding, chronic abdominal pain, and anorexia for 1 year. Her physical examination was notable for multiple cafe au lait spots. The colonoscopic and histopathologic examination revealed multiple adenomatous polyps that one of them contains low-high grade dysplasia and in situ carsinoma. Genetic analysis revealed a homozygous mutation in the PMS2 gene [c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)] and she was diagnosed with constitutional MMR gene defect syndrome. Polypectomy was performed 4 times in 2 years period. Then, the patient's last colonoscopic examination revealed a large broad polyp in the rectum and multiple polyps in the other colon segments, and she underwent colectomy because of high risk of colorectal cancer. Conclusions Adenomatous polyps are very important in childhood because of rarity. In particular, the presence of cafe au lait spots and a history of malignancy detected in relatives at an early age must be considered for CMMRD.

The authors of the original version of the above article requested the corrections in the first paragraph of “miRNA analysis” under the Results section and in Fig. 2 legend to be noted.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood, yet its etiology is unknown. It is known that microribonucleic acids (miRNAs) play a role in immunoregulation. We aimed to evaluate the plasma expression of some candidate miRNAs that are associated with the pathogenesis of autoimmunity. Thirty-one patients diagnosed with JIA and age-sex-matched 31 healthy children were enrolled for the study. The plasma levels of four candidate miRNAs (miRNA-16, miRNA-155, miRNA-204, and miRNA-451), which are known to be associated with autoimmunity, were examined in all the subjects. The plasma levels of miRNAs were measured with real-time PCR in the patients in active and inactive periods and in the healthy controls. The groups were compared with each other. The plasma miRNA-155 levels were found to increase in the JIA patients compared to the healthy controls, and it was statistically more significant in the inactive period. We found that the JIA patients had the higher levels of miRNA-16 and the lower levels of miRNA-204/miRNA-451 expressions compare with the control group, but there was no statistically significant difference. A statistically significant decrease in the plasma levels of miRNA-204 was found in the patients that were in inactive disease with only methotrexate therapy. The plasma miRNA expressions were compared in the JIA subtypes, and it was observed that miRNA-204 levels were higher in polyarticular JIA and miRNA-451 levels were higher in enthesitis-related arthritis without statistical significance. The significant alterations in the plasma expression of miRNA-155 and miRNA-204 suggest to us that these molecules may be related to the pathogenesis of JIA. More comprehensive and functional researches about the role of these molecules are needed in this regard.

TGFβ1 is an important cytokine acts as an antiinflammatory agent, and inhibits B cell proliferation. In patients with chronic lymphocytic leukemia (CLL), serum level of TGFβ1 are found elevated. Presence of G allele at position +915 in TGFβ1 gene results in arginine synthesis which is associated with higher expression of TGFβ1. We investigated the association of TGFβ1 +915G>C polymorphism with predisposition, clinical characteristics and laboratory findings of CLL. 50 CLL patients and 50 healthy controls were included in this study. Genotypes were determined by PCR-RFLP method. We couldn’t find statistically significant differences between patient and control groups in terms of genotype distributions and allele frequencies. However, GC genotype frequency was slightly higher in CLL patients than healthy controls. Furthermore, TGFβ1 +915GC genotype was found associated with trisomy 12 (p= 0.007). Further studies are needed to clarify exact role of TGFβ1 +915G>C polymorphism in patients with CLL.

Background/aims This study aimed to investigate polymorphisms in the genes responsible for encoding cytokines interleukin-6 (IL-6) (-572G/C) (rs1800796) and IL-17 (-197A/G) (rs2275913) in patients with celiac disease (CD). We further aimed to investigate the relationship between CD symptoms and histopathological findings and the relationship between these polymorphisms. Materials and methods We compared the results with those of healthy control subjects to establish whether any of the polymorphisms are involved in the susceptibility to CD. Eighty-four patients with CD and 83 healthy controls were enrolled in this study. Children with CD were divided into two groups depending on whether their symptoms were typical or atypical. The IL-6 (-572G/C) and IL-17 (-197A/G) polymorphisms were genotyped based on a polymerase chain reaction coupled with restriction fragment length polymorphism. Results Significant differences for the IL-6 (-572G/C) polymorphism were observed between patients with CD and controls (p=0.018, odds ratio (OR): 5.47, 95% confidence interval (CI): 1.161-25.800). No statistically significant association was observed between the IL-17 (-197A/G) polymorphism and CD (p>0.05). In addition, the symptoms and histopathological findings of children with CD were not related to either of the polymorphisms. Conclusion The results of our study indicate that the IL-6 (-572G/C) polymorphism may play a role in susceptibility to CD.

Michelin Tire Baby Syndrome is a rare congenital disorder and characterized clinically well defined multiple ring shaped skin creases. Our patient was born to onconsanguineous healthy parents as the third child of the family at 40 weeks of uneventful gestation with distinctive skin creases and gigantism. He was 4,950 g in weight (>90 percentile), 57.5 cm in length (>90 percentile), and had a head circumferences of 39.5 cm (>90 percentile) at birth. The physical examination showed a rough face, brachicephaly and craniosynostosis. His vital and laboratory findings were within normal limits at birth. Cranial and renal ultrasonograms, Xray graphics and cytogenetic analyses were normal. Echocardiography revealed small patent ductus arteriosis and patent foramen ovale. In this report, we present a new case of Michelin Tire Baby Syndrome who is the first neonate associated with severe gigantism and craniosynostosis, in the literature. A review of the related literature has also been presented.

Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatis) in children and is mainly idiopathic in most cases. Sometimes it may be associated with congenital anomalies, metabolic diseases or hereditary conditions. Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, “the odor of sweaty feet,” abdominal pain, vomiting, feeding intolerance, shock and coma. Recurrent acute pancreatitis associated with IVA have been rarely reported. Herein; we report a child who admitted with recurrent acute pancreatic attacks and had the final diagnosis of IVA. Mutation analysis revealed a novel homozygous mutation of (p.E117K [c.349G>A]) in the IVA gene. Organic acidemias must kept in mind in the differential diagnosis of recurrent acute pancreatic attacks in children.

WOS: 000365765400011, PubMed ID: 26539891, Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations., U.S. National Human Genome Research Institute (NHGRI) NHLBI grant [U54HG006542]; NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [RO1 NS058529, K23NS078056]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [5U54HG003273]; Medical Genetics Research Fellowship Program [T32 GM07526]; Regeneron, We thank all the family members and collaborators who participated in this study. This work was supported by U.S. National Human Genome Research Institute (NHGRI) NHLBI grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, NINDS grant RO1 NS058529 to J. R. L., and NHGRI 5U54HG003273 to R. A. G. T. H. is supported by the Medical Genetics Research Fellowship Program (T32 GM07526). W. W. is supported by Career Development Award K23NS078056 from NINDS. The authors would like to thank the ExAC and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. J.R.L. has stock ownership in 23andMe and Lasergen and is a paid consultant for Regeneron. J. R. L. is also a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Medical Genetics Laboratory (https://www.bcm.edu/geneticlabs/). W. K. C. is a paid consultant for Regeneron and BioReference Laboratories. C.G.-J. and J. D. O. are employees of the RGC.